Germline mutations in the MEN1 gene encoding menin predispose to endocrine tumors mainly of the parathyroids, anterior pituitary and entero-pancreatic endocrine tissues. We have investigated the molecular basis of this tissue specific tumorigenesis from menin loss in the pathogenesis of tumors of the pancreatic islet &#946;-cells (insulinoma). It is possible that the cause of the tissue-specificty is due to menin-mediated regulation of one or more tissue-specific factors such as those that control differentiation during embryogenesis. Therefore, we assessed the effect of menin loss or gain on the expression of factors that are known to control &#946;-cell differentiation. We found that the &#946;-cell differentiation factor HLXB9 (Mnx-1) is post-transcriptionally upregulated upon menin loss. HLXB9 causes apoptosis in the presence of menin, and it regulates genes that modulate insulin level. Thus, dysregulation of HLXB9 predicts a possible combined mechanism for &#946;-cell proliferation and constitutive insulin production in insulinomas. This would result from the possible blockade of the pro-apoptotic activity of HLXB9 upon menin loss, and increased insulin from increased HLXB9 upon menin loss. These findings advance the understanding of how a ubiquitously expressed protein such as menin controls tissue-specific tumorigenesis. Moreover, our data reveal the mechanisms of action of HLXB9 and its targets in &#946;-cells. We also showed that HLXB9 is phosphorylated by the kinase GSK-3&#946;, both phospho-HLXB9 and GSK-3&#946; are expressed in mouse and human &#946;-cell tumors, and GSK-3&#946; inhibitors reduced cell proliferation and delayed cell cycle progression of mouse &#946;-cell tumor cell lines. We are currently investigating the role of HLXB9 in sporadic pancreatic endocrine tumors, and the molecular mechanisms by which phospho-HLXB9 promotes tumorigenesis. These studies will provide insights into the pathways and actions of HLXB9 and its targets in normal &#946;-cells and in &#946;-cell tumors.